Matrix metalloproteinases (MMPs) are a group of structurally related endopeptidases that degrade the proteinaceous elements of the extracellular matrix. A number of important features are shared by members of the MMP family and these include a zinc atom at the catalytic site, catalytic activity at neutral pH, initial existence as inactive proenzymes, activation involving renewal of an N-terminal domain, structural stabilisation by calcium, and inhibition of the catalytically active forms by a family of specific protein inhibitors called Tissue Inhibitors of Metalloproteinases (TIMPs). The classical MMP family currently consists of at least twenty members including the collagenases, gelatinases, stromelysins and membrane-type MMPs.
The MMPs are a sub-family of a much larger group of zinc-containing proteinases which include the Reprolysins and Serralysins, and the Astacin family.
It has been demonstrated that some compounds which inhibit the classical MMPs also have the capability to inhibit a number of other events that are mediated by non-matrix metalloproteinases (MPs) which includes the release of TNFα, CSF-1 and TGFα, and the shedding of L-selectin and the IL-6, TNF-R1, and TNF-RII receptors. See Hooper et al (1997), Biochem. J., 321: 265-279.
Matrix metalloproteinases have been associated with many disease conditions. Inhibition of the activity of one or more of the MMPs could therefore be of benefit in these disease conditions. Such conditions include cancer, inflammation, autoimmune, infectious or ocular disease. See Whittaker M. et al, (1999) Chem. Rev., 99, 2735-2776 and (1994) Annals of the New York Academy of Sciences, Vol 732.
Thus compounds with MMP inhibitory properties may be used for treating a number of different diseases. Of particular benefit are those compounds which also have good pharmacokinetic properties.
However, the inhibition of non-matrix metalloproteinases (MPs) by these compounds may offer no therapeutic benefit and indeed could be deleterious. For example, it has been suggested that MMP inhibitors which also inhibit the release of TNFα may have a role in exacerbating liver injury; see Solorzano at al (1997), J. Immounol., 158:414-419.
Similarly, early clinical evidence from the use of MMP inhibtors, which are not selective for the classical MMPs alone, suggests that their use is associated, in many patients, with joint pain (tendonitis). See Wojtowicz-Praga et al, Lombardi Cancer Center, Georgetown University Hospital DC & BBL Anapolis Md. Am. Soc. Clin. Oncol. (May 1996) “The Pharmacokinetics (PK) of Marimastat (BB-2516), A Novel Metalloproteinase Inhibitor (MMPI) administered orally to patients with metastatic lung cancer”. The development of joint pain is dose-limiting and may require treatment “holidays”, for up to 50% of the course of treatment, or the administration of non-steroidal anti-inflammatory agents (NSAIDs).
There is therefore a need for selective MMP inhibitors which can be used in medicine at dosages at which they do not cause undesired side-effects, such as joint pain.
WO 99/24399 discloses a class of hydroxamic acid derivatives as MMP inhibitors.